Increased accumulation of adipose tissue macrophages (ATMs) promotes obesity-associated chronic inflammation and insulin resistance. Although there have been some advances in the study of ATMs in obese condition, the mechanisms underlying ATMs recruitment and activation remain to be determined. Thrombospondin 1 (TSP1) has been identified to be an adipokine and its expression levels correlate positively with human obesity, adipose tissue inflammation and insulin resistance. By using TSP1 deficient mice, preliminary studies revealed a novel role for TSP1 in stimulating macrophage recruitment and activation in adipose tissue that contributes to inflammation and insulin resistance resulting from high fat diet-induced obesity (DIO). Moreover, TSP1 promoting macrophage migration and activation is through the N-terminal domain and the type 1 repeats to interact with receptors LRP1 and CD36, respectively. Blocking the interactions of TSP1/LRP1 and TSP1/CD36 inhibited TSP1 stimulation of macrophage function. Based on these data, we hypothesize that blockade of the stimulatory effect of TSP1 on macrophage function prevents/ameliorates obesity-associated inflammation and insulin resistance. To test this hypothesis, in Aim 1, tissue specific TSP1 knockout mice will be used to definitively answer the question of whether adipocyte-derived TSP1 serves as a primary chemokine to stimulate macrophage accumulation in adipose tissue and promotes the development of obesity-associated inflammation and insulin resistance. In Aim 2, utilizing the identified stimulatory domains on TSP1 as targets, based on their available x-ray crystal structures, new decoy peptides will be designed by structure-based computational design strategy. The inhibitory effect of decoy peptides on TSP1stimulation of macrophage function will be tested. In Aim 3, whether blocking of TSP1/CD36 interaction can prevent/ameliorate obesity-associated inflammation and insulin resistance in vivo will be tested. Together, these proposed studies may lead to novel therapeutics for obesity-induced insulin resistance and metabolic complications, and therefore, have significant clinical relevance.